The United States Food and Drug Administration released a statement regarding a recently approved gene therapy drug, Zolgensma, intended to treat children less than two years of age with spinal muscular atrophy. It is a critical therapy meeting an unmet need.

However, the FDA was informed that the manufacturer, AveXis Inc., a subsidiary of Novartis, was aware of potential data issues before the drug was approved but chose to wait to notify the FDA until after approval. The issue regards data manipulation that impacts the accuracy of certain data from product testing performed in animals submitted in the biologics license application (BLA) and reviewed by the FDA.

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Timeline of Enforcement

FDA issued a particularly harsh press release on August 6, 2019 addressing the data accuracy issues with the BLA for the gene therapy product, Zolgensma, which was approved by FDA on May 24, 2019.

On June 28, 2019, AveXis informed FDA of “…a data manipulation issue that impacts the accuracy of certain data from product testing performed in animals submitted to the biologics licence application (BLA)…” FDA followed up with an inspection of the R&D site in San Diego, CA that began on July 24, 2019 and ended on August 2, 2019.

A 4-page form 483 resulted and addressed the failures to ensure accuracy and trustworthiness of the data. It is unusual that the form 483 was released before the 15 business days within which the firm must respond to FDA.

According to the press release, AveXis was aware of the data inaccuracies during FDA review but did not inform the Agency until after the product was approved. The Novartis press release states that “other health authorities” were also informed. Investigators for the FDA inspection were Scott Ballard and Mihaly Ligmond.

This form 483 should be read by all R&D staff who generate data that is included in regulatory filings to ensure an understanding of the importance of data integrity. The consequences “…may include civil or criminal penalties if appropriate,” according to a tweet from the FDA Commissioner. Novartis also issued a press release addressing the problem.

483 Observations

Observations from this inspection include but are not limited to:

Four non-conformances were opened to address the mismanaged or possibly manipulated In-Vivo Relative Potency Assay Studies. One investigation was opened approximately 2 months after the event was identified. The investigations were incomplete and did not assess other potential areas where data may have been miscalculated or manipulated. Rather, the investigation was limited to this small subset of data. Anyone who has followed the ‘data integrity’ area knows that FDA expects firms to take a more broad approach than this.
Laboratory records do not include complete data. Analytical balances do not have audit trails and printouts were not made and included in the logbook where weights are currently manually recorded. The equipment number of the analytical balance is not recorded in the logbook.
Vivarium staff who have responsibility for GMP functions report to the R&D Manager. R&D management identified in the observation have no direct experience operating in a GMP laboratory.
Laboratory reference standards have not been tested to ensure they meet release criteria. This lack of reference standard testing and release covers the past three years and are associated with potency values reported in the BLA.
Staff do not follow procedures for the recording of animal data.

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In the press release, the FDA also states “Ensuring truthful, complete and accurate data in product applications is a critical component of industry’s responsibility as they work to demonstrate the safety, purity, and potency of biological products. The submission of such truthful, complete and accurate data is also critical for the FDA to be able to protect the public health, and the law requires it. We are carefully assessing the issue of the manipulation of the product testing data used in the production process and are conducting a thorough assessment of the information from a recently completed inspection. In part, this will allow us to determine the implications for the FDA’s scientific review of the information in the BLA and will allow us to amend our publicly posted BLA reviews, as appropriate.”

Conclusion

It seems the FDA is using AveXis, and more importantly their parent company Novartis, as an example of what not to do. In GMP expert Barbara W. Unger’s experience, holding onto this information for two months while a high-visibility product is under review is mind-boggling. At least they didn’t say, as Immunogen did in 2018, that the investigation was protected by attorney-client privilege… that didn’t work out so well either!

The study with problems was part of a comparability study of the Phase 1 and Phase 3 material. It suggests someone manipulated the data so that the two materials were deemed comparability, when in reality they may not have been so. It would be interesting to know how much management pressure was put on people to make this happen – it seems easy to believe that was part of it, even if not clearly articulated that way.

This will likely have a painful end for both AveXis and Novartis. Again, this may be a useful lesson for R&D staff whose work is included in regulatory filings but who generally are not deeply involved in data integrity/data management issues.

Updates

August 19th, 2019: BIOPHARMADIVE reports that ‘Novartis replaced AveXis chief scientist, R&D head amid Zolgensma uproar.’ These were brothers, one of which was a co-founder of the firm. They were reportedly placed on administrative leave in May as Novartis conducted their investigation.